Alzheimer's disease (AD) and related neurodegenerative disorders are a major source of morbidity and mortality, particularly with the increasingly aged population of the United States. Pathology involving the microtubule-associated protein tau is a common feature of many such diseases, including AD, frontotemporal lobar degeneration, many forms of Parkinsonism, and amyotrophic lateral sclerosis. This proposal describes a training plan for the development of an academic neurologist interested in the molecular mechanisms of dementing diseases, particularly tau. The research plan focuses on the role of tau in AD pathology testing the hypothesis that tau is critical for the neuronal dysfunction induced by amyloid-beta (Abeta) in amyloid precursor protein (APP) transgenic mice. Preliminary studies indicate that tau removal prevents most behavioral and pathological abnormalities in APP mice at 4-7 months of age. Specific Aim 1 extends this observation, studying older APP mice to examine how long the effects of Abeta remain tau-dependent and determining the effect of changing tau expression after AD is produced and dysfunction is apparent. Specific Aim 2 considers signaling pathways that might mediate interactions between Abeta and tau, with an emphasis on the tyrosine kinase Fyn. Specific Aim 3 studies downstream mechanisms for tau's role, specifically regulation of axonal transport and APP processing. The candidate has a Ph.D. in neuroscience and an M.D. with residency training in neurology. He is committed to a career in academic medicine studying the basic mechanisms of neurodegenerative diseases. To that end, the research proposal and career development plan build on his prior training in basic neuroscience, biochemistry, electrophysiology, and clinical neurology to provide expertise in transgenic mouse models, behavioral analysis, histology, and viral vectors. Dr. Lennart Mucke, who specializes in transgenic mouse models of neurodegenerative disease, is the candidate's sponsor. The mentoring and research experience described in this proposal will facilitate the candidate's goal of an independent faculty research position.